The work proposed here will investigate the specificity of odorant recognition in the malaria mosquito Anopheles gambiae and correlate odor stimuli with quantifiable physiological and behavioral responses. This work will integrate complementary expertise in various relevant fields toward the common goal of thoroughly understanding the chemosensory system and chemosensory-mediated behavior of A. gambiae. Odor recognition specificity is very likely encoded in both odorant binding proteins (OBPs) and odorant receptors (ORs). Recent evidence suggests that odor recognition is a coordinated process that requires the combined specificities contributed by OBPs and ORs. OBPs are the first proteins of the olfactory system to encounter odor molecules, and data from our and other laboratories demonstrate that OBPs are critical for the olfactory response in A. gambiae. This makes the odorant binding proteins a preferred target for manipulating odor perception. Thus, in vitro expressed OBPs will be used in high-throughput screening assays to identify natural ligands and deduce binding capacities for known and newly identified ligands. Computer modeling studies allow us to design mutagenesis-based experiments to define amino acids associated with the OBP binding pocket and predict modified ligands with improved properties. In vivo validation of all in vitro studies will be obtained through electrophysiological and behavioral assays employing female mosquitoes that express normal levels of OBPs or are deficient in a specific OBP as a result of RNAi- mediated gene expression knockdown. Knowledge gained from this multi-disciplinary approach will lead to the identification of chemicals that can interfere with host seeking behavior by female mosquitoes, reducing the incidence of contact between the human host and the parasite vector.